Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies in our laboratory have documented the occurrence of naloxone-precipitated opioid abstinence from 45 minutes to 6 hours after acute morphine administration in humans. This study extended the morphine-naloxone interval to 24 hours and examined the effect of repeated naloxone challenges on withdrawal responses. Six male nondependent opiate users participated in eight experimental sessions in which they received single IM injections of morphine (18 mg/70 kg) followed 6 and 24 hours later by challenge sessions with IM placebo or naloxone (10 mg/70 kg). Naloxone challenge at 6 hours postmorphine reversed morphine-induced miosis and subjective reports of opiate symptoms, drug high, good drug effects, and drug liking. At 24 hours postmorphine, naloxone had no effect on these measures, which had returned to premorphine levels. However, at 6 and 24 hours postmorphine, naloxone precipitated subjective symptoms and observer-rated signs of opioid abstinence. When naloxone challenge at 24 hours was preceded by naloxone at 6 hours postmorphine, the magnitude of abstinence symptoms and signs was attenuated. These data suggest that morphine-induced adaptational changes underlying the development of physical dependence persist beyond other measureable agonist effects, and that these changes are disrupted or reversed by repeated antagonist administration.
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PMID:Acute opioid physical dependence in humans: effect of naloxone at 6 and 24 hours postmorphine. 235 13

Four monkeys, 2 rhesus and 2 cynomolgus, were trained to perform a multiple fixed-ratio extinction (MULT/FR/EXT) schedule for banana pellets. Subsequently, all animals were given hydromorphone (HYM) self-administration training, which consisted of substitution of FR (fixed ratio) 2 cocaine for FR 80 banana pellets and substitution of FR 2 HYM for FR 2 cocaine. All of the animals acquired cocaine self-administration. They also acquired HYM self-administration when it was substituted for cocaine. Next, 50 HYM self-maintenance sessions were given. During these sessions, animals were allowed to self-administer a total cumulative dose of 1 mg/kg/day of HYM. The animals were observed for spontaneous withdrawal while they performed an operant for food 24 and 48 hr after their last maintenance dose of HYM. Because none of the monkeys showed signs of spontaneous withdrawal or disruption of the appetitive baseline during the first postmaintenance appetitive session, a 0.4-mg dose of naloxone was administered noncontingently to test for precipitated withdrawal. Naloxone disrupted appetitive responding for banana pellets in the 2 rhesus monkeys. Naloxone had no effect on responding for food in the cynomolgus monkeys. Because none of the monkeys showed signs of spontaneous withdrawal or disruption of their appetitive baseline during the second postmaintenance session, a HYM challenge dose of 1 mg/kg was given noncontingently to assess whether tolerance to the daily maintenance dose had been acquired. The bolus dose of HYM suppressed lever pressing for food in both species, a result indicating a lack of tolerance. These results suggest that the positive reinforcing properties of HYM are sufficient to maintain opioid self-administration and that tolerance and physical dependence are not necessary.
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PMID:Nondependent monkeys self-administer hydromorphone. 244 22

These experiments examined the neurochemical mechanisms involved in the development and expression of place conditioning produced by heroin. Conditioned place preferences (CPP) lasting up to 8 weeks were obtained with doses of 50-1000 micrograms/kg heroin, using a regimen shown not to produce physical dependence. Naloxone pretreatment (50 micrograms/kg) during conditioning prevented the acquisition of heroin-induced CPP, but when given only on the test day, naloxone (50 or 1000 micrograms/kg) did not prevent the expression of heroin CPP. Clonidine disrupted the establishment of heroin CPP at 20 micrograms/kg, but disrupted its expression only at debilitating doses (100 and 200 micrograms/kg). Pimozide attenuated the acquisition (100 micrograms/kg) and expression (250 micrograms/kg) of heroin CPP. Together, these results support a role for opioid and catecholamine systems in the acquisition of heroin reinforcement, but they suggest that once heroin CPP is established, its expression in opiate-free subjects is not opiate receptor mediated and is relatively refractory to pharmacological treatments which disrupt acquisition. The data challenge the notion that the conditioned effects of opiates in drug-free animals are related to the release of endogenous opioids, and they also may help to explain why naloxone and clonidine are ineffective in the treatment of opiate addiction.
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PMID:Differential mechanisms in the acquisition and expression of heroin-induced place preference. 249 60

The effect of chronic administration of morphine and subsequent withdrawal on brain and pituitary receptors for thyrotropin releasing hormone (TRH) was investigated in Sprague-Dawley rats. The rats were implanted subcutaneously with four morphine pellets (each containing 75 mg of morphine free base) during a 3-day period. Placebo pellets, which contained all the excipients of morphine pellets except the morphine, were implanted in rats which served as controls. Both tolerance and physical dependence on morphine have been shown to develop as a result of this procedure. TRH receptors were labeled with 3H-(3-MeHis2) TRH (MeTRH). 3H-MeTRH bound to brain membranes at a single high affinity site with Bmax (receptor density) value of 24.6 +/- 2.2 fmol/mg protein and Kd (apparent dissociation constant) value of 3.7 +/- 0.4 nM. The binding of 3H-MeTRH to five regions of the brain namely, hypothalamus, cortex, striatum, midbrain and pons + medulla, as well as pituitary was also investigated. The binding of 3H-MeTRH to pituitary membranes was increased during the development of tolerance, whereas the binding to membranes prepared from different brain regions was unaffected. Serum concentration of triiodothyronine (T3) and thyroxine (T4) were found to be lower in chronic morphine-treated rats when compared to placebo-treated rats, however, serum TSH level remained unaltered. Twenty-four hours after the removal of morphine pellets (natural withdrawal), the binding of 3H-MeTRH to pons + medulla membranes was greater than in placebo control group. Naloxone-precipitated withdrawal produced results which were qualitatively similar to those obtained in rats from which pellets had been removed. The results suggest that the development of tolerance to morphine may be associated with changes in the pituitary-thyroid axis.
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PMID:The binding of 3H-(3-MeHis2) thyrotropin releasing hormone to brain and pituitary membranes of morphine tolerant-dependent and abstinent rats. 251 32

Rats were given daily injections of increasing doses of morphine sulfate (40-100 mg/kg, s.c.), for 4 days. Twenty hours after the last injection of morphine, the animals received bilateral injections of naloxone (1-10 micrograms) into the substantia nigra, ventral tegmental area or sites 2 mm rostral, caudal or dorsal to the site in the nigra. Withdrawal signs were monitored for 20 min after the intracerebral injection. Naloxone administered into the nigra in morphine-dependent rats produced dose-dependent significant increases in wet dog shakes, irritability to touch, teeth chattering, diarrhea and locomotion, compared to morphine-dependent animals that received injections of saline into the nigra. The injection of naloxone (3 micrograms) into the ventral tegmental area of morphine-dependent animals, produced irritability to touch and diarrhea, compared to morphine-dependent controls that received saline in this region of the brain. Significant differences in withdrawal signs were observed between morphine-dependent animals, that received injections of naloxone (3 micrograms) into the nigra and those that received naloxone (3 micrograms) into the ventral tegmental area or rostral or caudal sites. No differences between the substantia nigra and the dorsal sites were observed. However, withdrawal symptoms were produced by injections of naloxone into the substantia nigra and ventral tegmental area, even when the guide cannulae were angled to avoid penetration of sites dorsal to these regions of the brain. Naloxone, injected into the ventral midbrain of non-dependent animals, produced no signs of withdrawal. These studies suggest that the ventral midbrain mediates physical dependence on morphine.
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PMID:Evidence that physical dependence on morphine is mediated by the ventral midbrain. 259 60

Acute opioid physical dependence refers to the withdrawal symptoms precipitated by an opioid antagonist administered after a single dose or short-term infusion of an opioid agonist. This phenomenon is particularly interesting given that the abstinence syndrome has generally been thought to develop only after chronic exposure to opioid agonists. The purpose of this study was to determine the minimum time after agonist administration when antagonist-precipitated withdrawal could be observed. Naloxone (10 mg/70 kg) was administered i.m. either 0, 15, 45 or 90 min after single i.m. injections of morphine (18 mg/70 kg) in five nondependent male opiate users. Physiological and subjective report measures revealed no effect of morphine or naloxone at the 0 and 15 min morphine-naloxone interval conditions; however, before the naloxone challenge 45 and 90 min post-morphine, agonist effects (e.g., miosis, respiratory depression and good drug effect subjective ratings) were clearly evident. Naloxone reversed these effects to premorphine levels and simultaneously precipitated subjective symptoms and observer rated signs of opiate withdrawal. Thus, this study showed that antagonist-precipitated withdrawal in humans was first observed 45 min after agonist administration. Further, the onset of naloxone-precipitated withdrawal effects closely paralleled the onset of morphine agonist effects. The results of this study suggest that adaptational changes underlying the development of physical dependence begin within minutes after acute exposure to an opiate.
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PMID:Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval. I. 276 Aug 39

Intracellular recordings of membrane potassium current were made from rat locus coeruleus in vitro. The effects of agonists at mu-opioid receptors were studied on neurons from rats that had been chronically treated with morphine; these were compared with actions on neurons from control rats. Tolerance to the opioid-induced increase in potassium conductance was observed, and this was more pronounced for normorphine than for [Met5]enkephalin and [D-Ala2, Mephe4, Gly5-ol]enkephalin: experiments with the irreversible receptor blocker beta-chlornaltrexamine indicated that normorphine had lower intrinsic efficacy than [Met5]enkephalin and [D-Ala2 MePhe4, Gly5-ol]enkephalin. This adaptation was not due to any change of the properties of the potassium conductance activated by mu-receptors because both full and partial agonists at alpha 2-adrenoceptors, which couple to the same potassium conductance, were unchanged in their effectiveness; nor was it associated with any change in the affinity of mu-receptors for the antagonist naloxone. Naloxone had no effect on the neurons other than simple competitive reversal of the action of the mu-receptor agonists. These results demonstrate that 1) the mechanism responsible for tolerance in locus coeruleus neurons is specifically associated with mu-receptors and/or their coupling to potassium channels, 2) the intrinsic efficacy of an opioid determines the degree of tolerance observed, and 3) tolerance and physical dependence can be dissociated at the cellular level.
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PMID:Cellular mechanisms of opioid tolerance: studies in single brain neurons. 282 80

Spiradoline (a congener of the kappa opioid agonist, U-50488H) was evaluated for analgesic and related activities in rodents. In nine antinociceptive assays utilizing various thermal, pressure and chemical and physical irritants, the potency of spiradoline ranges from 4.7 to 23 (mean = 13) times that of U-50488H. Naloxone blocks the analgesic effect of spiradoline. The in vivo naloxone pA2 for this antagonism is much lower than that for the antagonism of morphine and approximates that of U-50488H. The analgesic potency of spiradoline is greatly reduced in mice made tolerant to U-50488H but not in those made tolerant to morphine. Repeated treatment with spiradoline does not induce physical dependence as evidenced by a lack of naloxone-precipitated jumping and withdrawal-induced hyperalgesia. In sum, these observations suggest that spiradoline is a potent kappa agonist analgesic. However, further evaluation of spiradoline revealed differences between this compound and U-50488H. We have previously shown that the analgesic effect of the latter compound, but not that of morphine, is profoundly antagonized by reserpine or p-chlorophenylalanine. In contrast, spiradoline is only marginally antagonized by these serotonin-depleting treatments. Evaluation of the enantiomers of spiradoline revealed that the (-)-enantiomer is more than 30 times as potent as the (+)-enantiomer in analgesic tests. The (-)-enantiomer is similar to U-50488H with regard to antagonism by p-chlorophenylalanine, lack of physical dependence-inducing properties and cross-tolerance. In contrast the (+)-enantiomer induces physical dependence and displays marked cross-tolerance in morphine-tolerant mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analgesic and mechanistic evaluation of spiradoline, a potent kappa opioid. 283 65

1. The antinociceptive effects of [D-Arg2] dermorphin tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-beta-Ala-OH when administered subcutaneously (s.c.) in rats were measured by the tail-flick test. In addition, the appearance of typical withdrawal signs upon cessation of administration or on subsequent treatment with naloxone were measured after chronic administration of either peptide or morphine. 2. The dose of peptides and of morphine in the physical dependence test was determined from the AD50 to inhibit the tail-flick test in rats. Doses from 4 to 64 times the AD50 doses were employed in the s.c. administration schedules. 3. The intensity of the antinociception induced by either peptide was greater than that produced by morphine. Moreover, the antinociception induced by the peptides was of much longer duration than that produced by morphine. 4. Abrupt withdrawal after chronic administration of either peptide produced only slight loss of body weight. In contrast, morphine withdrawal produced sharp loss of body weight. 5. Naloxone precipitated withdrawal signs after chronic administration of either peptide were less intense than those after chronic morphine. 6. These results suggest that the antinociception produced by these peptides is more intense and of longer duration than that produced by morphine. It is also interesting to note that the physical dependence produced by these peptides is less marked than that produced by morphine.
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PMID:Antinociception and physical dependence produced by [D-Arg2] dermorphin tetrapeptide analogues and morphine in rats. 290 1

Antagonist-precipitated withdrawal after acute opioid administration (acute physical dependence) is an interesting phenomenon in that the opioid abstinence syndrome is generally thought to develop only after prolonged exposure to opioid agonists. The purpose of this study was to examine further this phenomenon in humans by characterizing the antagonist dose-response function. The effects of i.m. naloxone (0, 0.1, 0.3, 1, 3, 10 and 30 mg/70 kg) were assessed 6 hr after single i.m. injections of morphine (18 or 30 mg/70 kg) in six subjects with a history of chronic opiate use. Naloxone reversed residual morphine effects, including miosis and respiratory depression. The degree of reversal was dose-related to 10 mg/70 kg of naloxone with no further increases at the highest naloxone dose. Simultaneously, observer ratings of withdrawal signs and subjective reports of withdrawal symptoms were increased in an orderly dose-related manner to 30 mg/70 kg of naloxone. Reversal of residual morphine effects and onset of precipitated withdrawal were evident by 5-min postnaloxone; peak effects occurred within 15 min. This study confirmed the occurrence of antagonist-precipitated withdrawal after brief opioid exposure in humans, demonstrated the rapid onset of withdrawal effects and characterized the naloxone dose-response function.
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PMID:Acute opioid physical dependence in postaddict humans: naloxone dose effects after brief morphine exposure. 291 67


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